Phase 1/1b study of SY-5609, a selective and potent CDK7 inhibitor, in advanced solid tumors and in 2L/3L pancreatic ductal adenocarcinoma (PDAC) in combination with gemcitabine +/- nab-paclitaxel.
Authors: Babar Bashir, Manish Sharma, Dejan Juric, Kyriakos P. Papadopoulos, Erika P. Hamilton, Debra L. Richardson, Geoffrey Shapiro, Vaibhav Sahai, Niharika B. Mettu, Zev A. Wainberg, Olatunji B. Alese, Tomislav Dragovich, Graeme Hodgson, Susan Henry, Terence Hall, Sofia Paul, David A. Roth, Michael Kelly, Tanya Abdul Malak, Virginia Klimek
Journal: Journal of Clinical Oncology (2023)

3080 Background: SY-5609 is an oral, highly selective and potent noncovalent inhibitor of CDK7, a key regulator of cell cycle progression and transcription. In this Phase 1 FIH study (NCT04247126), the single agent (SA) continuous daily dosing (CDD) regimen maximum tolerated dose (MTD) was 3 mg/day. Subsequently, enhanced tolerability was demonstrated using an intermittent 7 day on/7 day off (7/7) schedule at higher dose levels (Sharma 2021). SY-5609 preclinical data and early clinical activity provided the rationale for evaluating SY-5609 + gemcitabine (gem) +/- nab-paclitaxel (np) in PDAC. Herein, we present data from the ongoing SA dose escalation and SY-5609 + gem +/- nab-paclitaxel (np) safety lead-ins (SLIs). Methods: The 7/7 schedule was used to further evaluate SA escalation in pts with select solid tumors. In the PDAC combination SLIs, SY-5609, starting with a dose of 4 mg, is escalated using the 7/7 schedule in combination with biweekly gem (1000 mg/m 2 ) +/- np (125 mg/m 2 ). Evaluations included safety, clinical activity (RECIST v1.1), PK, and induction of peripheral blood PD marker POLR2A (Papadopoulos 2020). Results: As of 13 Jan 2023, 87 pts have been enrolled (70 SA, 14 SY-5609 + gem, 3 SY-5609 + gem/np), including 30 pts across the 4, 5, 6, 7, and 10 mg SA 7/7 cohorts included in the safety summary. MTD for the 7/7 schedule has not been reached. The 15 mg SA cohort is now enrolling. Most SA 7/7 AEs were low-grade; AEs included (&gt;20%) nausea, diarrhea, fatigue, anorexia, and thrombocytopenia. No new safety signals were observed in the SY-5609 4 mg and 5 mg + gem and SY-5609 4 mg + gem/np cohorts; 1 pt (SY-5609 5 mg + gem) had a DLT of Gr3 diarrhea. The 10 mg + gem cohort is now enrolling. Most SY-5609 + gem +/- np AEs were low grade. AEs in the SLIs were consistent with the safety profile of either SY-5609 or gem +/- np and included (&gt;20%) fatigue, anorexia, nausea, abdominal pain, and constipation. In the SA cohorts (response-evaluable, n=29), 100% (3/3) of pts in the 10 mg 7/7 cohort had stable disease (SD) as the best response, compared to 19% (5/26) SD rate in 4 to 7 mg SA 7/7 cohorts. Disease control rate in the combination SLIs (response-evaluable, n=11) was 45% (5/11), including 1 confirmed partial response (4 mg + gem) in a patient with liver metastases who had a reduction in CA 19-9 from 60,357 U/mL to 968 U/mL, and SD in 4 pts (3 in 5 mg + gem, 1 in 4 mg + gem/np). SA and SLI PK data support an emerging exposure-activity relationship. POLR2A PD marker data from SA and SLI cohorts correlate with exposure. Conclusions: To date, intermittent dosing of SY-5609 on the 7/7 schedule has acceptable tolerability alone and in combination with gem +/- np. Encouraging preliminary clinical activity and the emerging exposure-activity relationship supports the ongoing escalation of SY-5609 in SA and combination SLI cohorts; updated results will be presented. Clinical trial information: NCT04247126 .